This invention relates generally to anti-inflammatory compounds and pharmaceutical compositions, and more particularly to anti-inflammatory compounds and compositions which are capable of inhibiting leukotriene A4 hydrolase.
LTA4 hydrolase is a requisite enzyme in the biosynthetic pathway leading to LTB4 formation. LTB4 is a proinflammatory compound. R. Lewis, et al., N. Engl. J. Med. 323, 645-655 (1990) have demonstrated that LTB4 is a potent granulocyte agonist inducing chemotaxis, aggregation, degranulation, adherence and priming of inflammatory cells for induction by other agonists. Binding of LTB4 to receptors is stereospecific with two distinct classes of binding sites. A. Lin, et al., Prostaglandins 28, 837-849 (1984). A high affinity site [4-5xc3x9710xe2x88x9210 M] mediates chemotaxis and chemokinesis while lower affinity sites [0.6-5xc3x9710xe2x88x927 M] stimulate granular secretion and oxidative burst. The LTB4 receptor is associated with a GTP-binding protein that regulates affinity and transduces signals. T. Schepers, et al., J. Biol. Chem. 267, 159-165 (1992). Elevated LTB4 levels have been reported for many diseases. Most prominently, elevated LTB4 levels have been correlated to the pathology of inflammatory bowel disease (IBD) including Cohn""s disease and ulcerative colitis and in psoriasis. P. Sharon, et al., Gastroent. 86, 453-460; K. Lauritsen, et al., Gastroent. 95, 11-17 (1989); S. Brain, et al., Br. J. Pharm., 83, 313-317 (1984). Other properties of LTB4 which may contribute to disease processes are: stimulation of mucus secretion; stimulation of cytokine production; and the ability to act synergistically with other inflammatory mediators such as prostaglandins and cysteinyl leukotrienes thereby amplifying the inflammatory process.
B. Samuelsson, et al., J. Biol Chem., 264, 19469-19472 (1989) have shown that LTB4 biosynthesis from arachidonic acid involves the action of 2 enzymes, 5-lipoxygenase [5-LO] and LTA4 hydrolase. 5-LO transforms arachidonic acid to 5-HPETE and subsequent formation of LTA4, which is an unstable allylic epoxide intermediate which is enzymatically hydrolyzed by LTA4 hydrolase to form the dihydroxy acid LTB4.
LTA4 hydrolase is distinct from cytosolic and microsomal epoxide hydrolases based on strict substrate requirements, product formation [5(S),12(R) vs. 5(S),6(R) for mouse liver cytosolic epoxide hydrolase, and lack of inhibition by inhibitors of cytosolic epoxide hydrolase. LTA4 hydrolase appears to be ubiquitously distributed in mammalian tissues even in cell types that do not express 5-LO, suggesting the importance of transcellular metabolism of LTA4. While peptidomimetic compounds such as bestatin and captopril have been shown to exhibit LTA4 hydrolase inhibitory activity, they are not able to satisfy the requirement of a small organic compound which is capable of cellular penetration. It would therefore be very advantageous to be able to provide low molecular weight inhibitors of LTB4 biosynthesis which preferably exhibit oral activity in vivo at desirably low concentrations.
Applicants have now discovered that compounds of the formula I
Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Zxe2x80x83xe2x80x83(I)
and pharmaceutically acceptable salts and stereoisomers thereof possess LTA4 hydrolase inhibitor activity, wherein:
Ar1 is an aryl moiety selected from the group consisting of:
(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from the group consisting of Cl, Br, F, CF3, lower alkyl, lower alkoxy, NH2, NO2 and OH;
(ii) 2-, 4- or 5-thiazolyl,
(iii) 2-, 3- or 4-pyridinyl,
(iv) 2- or 3-thienyl, and
(v) 2- or 3-furyl;
Ar2 is an aryl moiety selected from the group consisting of: 
Q is selected from the group consisting of:
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94CH2xe2x80x94,
(iii) xe2x80x94OCH2xe2x80x94,
(iv) xe2x80x94CH2Oxe2x80x94,
(v) xe2x80x94NHxe2x80x94;
(vi) xe2x80x94NHCH2xe2x80x94,
(vii) xe2x80x94CH2NHxe2x80x94,
(viii) xe2x80x94CF2xe2x80x94,
(ix) xe2x80x94CHxe2x95x90CHxe2x80x94,
(x) xe2x80x94CH2CH2xe2x80x94, and
(xi) carbon-carbon single bond;
Y is selected from the group consisting of
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94Sxe2x80x94,
(iii) xe2x80x94NHxe2x80x94,
(iv) xe2x80x94S(O)xe2x80x94, and
(v) xe2x80x94S(O2)xe2x80x94;
R is selected from the group consisting of:
(i) linear or branched C2-C6 alkylene; or
(ii) C(R10)(R11)xe2x80x94(CH2)m; and
Z is selected from the group consisting of: 
(vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;
wherein R1 and R2 are independently selected from the group consisting of:
(i) H,
(ii) lower alkyl or allyl,
(iii) benzyl,
(iv) xe2x80x94(CH2)aCOR15,
(v) 
(vi) xe2x80x94(CH2)axe2x80x94OH
R3 and R4 are independently H or lower alkyl;
R5 and R6 are independently selected from the group consisting of: 
R7 is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy, or R7 taken together with R10 is an alkylene group having one or two carbon atoms;
R8 and R9 are independently H, halogen, lower alkyl, lower alkoxy, NH2, NO2 or OH;
R10 is H, lower alkyl, or R10 taken together with R7 is an alkylene group having one or two carbon atoms;
R11 is H or lower alkyl;
R12 is selected from the group consisting of:
(i) H,
(ii) xe2x80x94OH or xe2x95x90O,
(iii) xe2x80x94(CH2)aCOR15,
(iv) xe2x80x94(CH2)aCONH(CH2)bCO2R16,
(v) xe2x80x94NHR17;
R13 and R14 are independently hydrogen, xe2x80x94(CH2)aCOR15, provided that at least one of R13 and R14 is hydrogen;
R15 is xe2x80x94OR16 , xe2x80x94NHR16 or xe2x80x94NHNH2;
R16 is H, lower alkyl or benzyl;
R17 is H, lower alkyl, benzyl, xe2x80x94COR16 or xe2x80x94CONH2;
X1 is 
xe2x80x83xe2x80x94Sxe2x80x94, or xe2x80x94Oxe2x80x94, wherein R18 is H, lower alkyl, xe2x80x94CONH2, CSNH2, xe2x80x94COCH3 or xe2x80x94SO2CH3;
a and b are independently integers of from 0 to 5;
m is 1, 2 or 3;
n is 0, 1, 2 or 3;
p is 1 or 2; and
q is 1, 2 or 3;
provided however that where R is C(R10)(R11)xe2x80x94(CH2)m, and R10 taken together with R7 forms an alkylene group having one or two carbon atoms, then xe2x80x94Ar2xe2x80x94Yxe2x80x94R is 
wherein X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94, and r is 1 or 2, further provided that wherein R1, R2 or both R1 and R2 are xe2x80x94(CH2)aCOR15, then a is not O.
In one of its embodiments, the present invention entails compounds of the formula I
Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Zxe2x80x83xe2x80x83(I)
and pharmaceutically acceptable salts and stereoisomers thereof, wherein:
Ar1 is an aryl moiety selected from the group consisting of:
(i) phenyl, mono-, di-, or tri-substituted phenyl with the substituents selected from the group consisting of Cl, Br, F, CF3, lower alkyl, lower alkoxy, NH2, NO2 and OH;
(ii) 2-, 4- or 5-thiazolyl,
(iii) 2-, 3- or 4-pyridinyl,
(iv) 2- or 3-thienyl, and
(v) 2- or 3-furyl;
Ar2 is an aryl moiety selected from the group consisting of: 
Q is selected from the group consisting of:
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94CH2xe2x80x94,
(iii) xe2x80x94OCH2xe2x80x94,
(iv) xe2x80x94CH2Oxe2x80x94,
(v) xe2x80x94NHxe2x80x94;
(vi) xe2x80x94NHCH2xe2x80x94,
(vii) xe2x80x94CH2NHxe2x80x94,
(viii) xe2x80x94CF2xe2x80x94,
(ix) xe2x80x94CHxe2x95x90CHxe2x80x94,
(x) xe2x80x94CH2CH2xe2x80x94, and
(xi) carbon-carbon single bond;
Y is selected from the group consisting of
(i) xe2x80x94Oxe2x80x94,
(ii) xe2x80x94Sxe2x80x94,
(iii) xe2x80x94NHxe2x80x94,
(iv) xe2x80x94S(O)xe2x80x94, and
(v) xe2x80x94S(O2)xe2x80x94;
R is selected from the group consisting of:
(i) linear or branched C2-C6 alkylene; or
(ii) C(R10)(R11)xe2x80x94(CH2)m; and
Z is selected from the group consisting of: 
(vii) a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, wherein the heteroatom is nitrogen, and wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring;
wherein R1 and R2 are independently selected from the group consisting of:
(i) H,
(ii) lower alkyl or allyl,
(iii) benzyl, 
R3 and R4 are independently H or lower alkyl;
R5 and R6 are independently selected from the group consisting of: 
R7 is H, halogen, lower alkyl, lower alkoxy, nitro, hydroxy, or R7 taken together with R10 is an alkylenyl group having one or two carbon atoms;
R8 and R9 are independently H, halogen, lower alkyl, lower alkoxy, NH2, NO2 or OH;
R10 is H, lower alkyl, or R10 taken together with R7 is an alkylenyl group having one or two carbon atoms;
R11 is H or lower alkyl;
R12 is selected from the group consisting of:
(i) H,
(ii) xe2x80x94OH or xe2x95x90O,
(iii) xe2x80x94(CH2)aCOR15,
(iv) xe2x80x94(CH2)aCONH(CH2)bCO2R16,
(v) xe2x80x94NHR17;
R13 and R14 are independently hydrogen, xe2x80x94(CH2)aCOR15, provided that at least one of R13 and R14 is hydrogen;
R15 is xe2x80x94OR16, xe2x80x94NHR16 or xe2x80x94NHNH2;
R16 is H, lower alkyl or benzyl;
R17 is H, lower alkyl, benzyl, xe2x80x94COR16 or xe2x80x94CONH2;
X1 is 
xe2x80x94Sxe2x80x94, or xe2x80x94Oxe2x80x94, wherein R18 is H, lower alkyl, xe2x80x94CONH2, CSNH2, xe2x80x94COCH3 or xe2x80x94SO2CH3;
a and b are independently integers of from 0 to 5;
m is 1, 2 or 3;
n is 0, 1, 2 or 3;
p is 1 or 2; and
q is 1, 2 or 3;
provided however that where R is C(R10)(R11)xe2x80x94(CH2)m, and R10 taken together with R7 forms an alkylenyl group having one or two carbon atoms, then xe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94 is 
wherein X is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94, and r is 1 or 2, further provided that wherein Z is 
and R1 and/or R2 is xe2x80x94(CH2)aCOR15, then a is not O.
In one of its embodiments the present invention entails compounds of formula I Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Z, wherein Z is an amine moiety of the formula 
In another of its embodiments the present invention includes compounds of formula I Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Z, wherein Z is 
wherein R3, R4, R5 and R6 are defined as set forth hereinbefore.
In another of its embodiments the present invention entails compounds of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Z wherein when Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Y is 
then (A) R1 and R2 are not simultaneously H or lower alkyl; or (B) R3, R4, R5 and R6 are not simultaneously H.
The compounds of the present invention, in several embodiments, may comprise a carboxylic acid or ester moiety. It will be appreciated by the art-skilled that a compound of the present invention comprising an ester moiety is readily converted, in vivo, especially when administered orally, into its corresponding carboxylic acid form. The ester-containing compounds of the present invention are therefore prodrugs of their carboxylic acid form.
In another of its embodiments the present invention concerns compounds of formula I Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Z, wherein Z is a monocyclic or bicyclic heteroaromatic moiety having at least one heteroatom, the at least one heteroatom being nitrogen, wherein the monocyclic heteroaromatic moiety comprises a 5- or 6-membered ring and the bicyclic heteroaromatic moiety comprises a fused 9- or 10-membered ring.
In another of its aspects the invention entails pharmaceutical composition comprising a pharmacologically effective amount of a compound of formula I and a pharmaceutically acceptable carrier.
In still another of its embodiments the present invention involves a method for treating a mammal exhibiting an LTB4 mediated inflammatory condition comprising administering to the mammal a pharmacologically effective amount of a compound of formula I.
The term xe2x80x9clower alkylxe2x80x9d means straight or branched chain alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, pentyl, hexyl and the branched chain isomers thereof.
The term xe2x80x9clower alkoxyxe2x80x9d means straight or branched chain alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the branched chain isomers thereof.
The term xe2x80x9callylxe2x80x9d as used herein means the 1-propenyl radical, xe2x80x94CH2xe2x80x94CH2xe2x95x90CH2.
The term xe2x80x9chaloxe2x80x9d means fluoro, cloro, bromo, or iodo.
The phrase xe2x80x9cmonocyclic or bicyclic heteroaromatic moietyxe2x80x9d having at least one heteroatom which is nitrogen, includes but is not limited to imidazole, triazole, benzimidazole, imidazopyridine, triazolopyridine, thiazole, purine and the like. Such monocyclic and bicyclic heteroaromatic moieties having at least two nitrogen atoms may be bonded, in a compound of the present invention, through any of the nitrogen atoms, as will be appreciated by the person of ordinary skill in the art, to provide two or more conformational isomers.
Such monocyclic heteroaromatic and bicyclic heteroaromatic compounds are included in the group of compounds referred to herein as xe2x80x9cZHxe2x80x9d, which group also includes non-aromatic compounds. Non-aromatic compounds which are contemplated by reference to xe2x80x9cZHxe2x80x9d include acyclic amines, monocyclic amines, and bicyclic amines as defined herein. A compound of formula I, which comprises a xe2x80x9cZ moietyxe2x80x9d may be readily formed by reacting a compound of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Rxe2x80x94Cl or Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Rxe2x80x94OTs with an amine or heteroaromatic compound, ZH.
Included within the classes and subclasses of compounds embraced by Formula I are isomeric forms of the described compounds including diastereoisomers, enantiomers and tautomeric forms of the described compounds. Pharmaceutically acceptable salts of such compounds are also included as well as pharmaceutically acceptable salts of such isomers and tautomers.
In the structures herein a bond drawn across a bond in a ring indicates that the bond can be to any available atom of the ring structure.
The expression xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d is intended to include those salts capable of being formed with the compounds of the present invention without materially altering the chemical structure or pharmacological properties thereof. Such salts include inorganic and organic cations or acid addition salts, such as sodium, potassium, calcium, ammonium, alkylammonium, quaternary ammonium, triethanolamine, lysine, hydrochloride, hydrobromide, etc. well known to those skilled in the art. The foregoing salts are prepared in the conventional manner by neutralization of the compounds of formula I with the desired base or acid.
The compounds of the present invention can be administered to a patient in such oral dosage forms as tablets, capsules, pills, powders, granules, elixirs or syrups, as well as aerosols for inhalation. Likewise, administration may be effected intravascularly, subcutaneously, or intramuscularly using dosage forms known to those of ordinary skill in the pharmaceutical arts. In general, the preferred form of administration is oral. An effective but non-toxic amount of the compound is employed in treatment. The dosage regimen utilizing the present compounds is selected in accordance with a variety of factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition to be ameliorated; and the route of administration. A physician of ordinary skill can readily determine and prescribe a xe2x80x9cpharmaceutically effective amountxe2x80x9d of a compound of Formula I, that is, the effective amount of the compound required to prevent, treat or arrest the progress of the condition. Dosages of the compounds of the present invention will range generally between 0.1 mg/kg/day to about 100 mg/kg/day and preferably between about 0.5 mg/kg/day to about 50 mg/kg/day when administered to patients suffering from allergic or hypersensitivity reactions or inflammation. The compounds may also be administered transdermally or topically to treat proliferative skin conditions such as psoriasis. The daily dosage may be administered in a single dose or in equal divided doses three to four times daily.
As used herein the phrase xe2x80x9cLTA4 hydrolase inhibitorxe2x80x9d means a compound which is capable of exhibiting an IC50 of less than 1 mM in an in vitro assay employing 10 xcexcg/ml of LTA4 hydrolase enzyme (specific activity 600 nMoles LTB4/min/mg of enzyme) in the presence of 25 xcexcM substrate (LTA4) in a total reaction volume of 100 xcexcl.
In the pharmaceutical compositions and methods of the present invention, at least one of the active compounds of formula I or a pharmaceutically acceptable salt thereof will typically be administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as xe2x80x9ccarrierxe2x80x9d materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol and the like; for oral administration in liquid form, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier such as ethanol and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintigrating agents and coloring agents can also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Lubricants for use in these dosage forms include boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintigrators include, without limitation, starch, methylcellulose, agar, bentonite, guar gum and the like.
By virtue of their activity as LTA4 hydrolase inhibitors, the compounds of Formula I are useful in treating inflammatory conditions mediated by LTB4 production in mammals such as psoriasis, contact and atropic dermatitis, Crohn""s disease, ulcerative colitis, inflammatory bowel disease, multiple sclerosis, ankylosing spondylitis arthritis, asthma and the like. Similarly, the compounds of Formula I can be used in preventing recurring inflammatory attacks. A physician or veterinarian of ordinary skill can readily determine whether a subject exhibits the inflammatory condition. A preferred utility relates to treatment of ulcerative colitis.
Among the compounds of the present invention which possess LTA4 hydrolase inhibiting activity are the following:
1-[2-(4-phenoxyphenoxy)ethyl]pyrrolidine;
1-[2-(4-phenylmethyl)phenoxyethyl]pyrrolidine;
1-[2-[4-(2-phenylethenyl)phenoxy]ethyl]pyrrolidine;
1-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]pyrrolidine;
4-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methyl]thiazole;
1-[2-[4-(phenylmethoxy)phenoxy]ethyl]pyrrolidine;
4-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzoic acid;
4-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]benzoic acid;
5-phenoxy-2-[2-(1-pyrrolidinyl)ethoxy]pyridine;
1-[2-[4-(2-phenylethyl)phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(difluoro)phenylmethyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-(phenylmethyl)phenylthio]ethyl]pyrrolidine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenylsulfinyl]ethyl]pyrrolidine, monohydrochloride;
N-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methyl]-3-pyridinamine;
N-(4-phenoxyphenyl)-1-pyrrolidine ethanamine, monohydrochloride;
5-(phenylmethyl)-2-[2-(1-pyrrolidinyl)ethoxy]thiazole;
1-[2-[2-fluoro-4-(phenylmethyl)phenoxy]ethyl]pyrrolidine;
1-[2-[3-fluoro-4-(phenylmethyl)phenoxy]ethyl]pyrrolidine;
1-[2-[2-methyl-4-(phenylmethyl)phenoxy]ethyl]pyrrolidine;
1-[2-[2,6-difluoro-4-(phenylmethyl)phenoxy]ethyl]pyrrolidine;
2-[4-[2-(1-pyrrolidinyl)ethoxy]phenylmethyl]thiazole;
5-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methyl]thiazole;
methyl 5-(phenylmethyl)-2-[2-(1-pyrrolidinyl)ethoxy]benzoate;
3-[4-[2-(1-pyrrolidinyl)ethoxy]phenylmethyl]pyridine;
4-[4-[2-(1-pyrrolidinyl)ethoxy]phenylmethyl]pyridine;
1-[2-[4-[(3-methoxyphenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[4-(methoxyphenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-methoxyphenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(1,3-benzodioxol-5-yl)methyl]phenoxy]ethyl]pyrrolidine;
2-[4-[2-(1-pyrrolidinyl)ethoxy]phenylmethyl]quinoline;
3-[4-[2-(1-pyrrolidinyl)ethoxy]phenylmethyl]quinoline;
1-[2-[4-[(2-thiophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-thiophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-furanyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-furanyl)methyl]phenoxy]ethyl]pyrrolidine;
2-[[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methyl]pyridine;
1-[2-[4-[(4-fluorophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(4-chlorophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-fluorophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-fluorophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-chlorophenyl)methyl]phenoxy]ethyl]pyrrolidine;
1-[2-[[5-(phenylmethyl)pyridin-2-yl]oxy]ethyl]-4-piperidine-carboxamide;
1-[2-[4-(2-naphthalenyl)methoxy]phenoxyethyl]pyrrolidine;
3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxymethyl]quinoline;
2-methyl-4-[[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]methyl]thiazole;
1-[2-[4-[(4-bromophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2,6-dichlorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(4-fluorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-chlorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-fluorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-chlorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[[(3-trifluoromethyl)phenyl]methoxy]phenoxy]ethyl]-pyrrolidine;
1-[2-[4-[(2-methylphenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(3-fluorophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(4-methylphenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(4-methoxyphenyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(1-naphthyl)methoxy]phenoxy]ethyl]pyrrolidine;
1-[2-[4-[(2-thiophenyl)methoxy]phenoxy]ethyl]pyrrolidine;
methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2S-pyrrolidine-2-carboxylate, monohydrochloride, hydrate;
1-[3-[4-(phenylmethyl)phenoxy]propyl]-4-piperidine-carboxamide;
N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrrolidin-3-yl]acetamide, monohydrochloride;
phenylmethyl 1-[3-[4-(phenylmethyl)phenoxy]propyl]-L-prolinate;
1-[2-[4-[(2-thiophenyl)methyl]phenoxy]ethyl-4-piperidine-carboxamide;
1-[2-[4-[(3-thiophenyl)methyl]phenoxy]ethyl]-4-piperidine-carboxamide;
1-[2-[4-[(2-thiazolyl)methyl]phenoxy]ethyl]-4-piperidine-carboxamide;
1-[2-[4-[(4-methoxyphenyl)methyl]phenoxy]ethyl]-4-piperidine-carboxamide;
1-[2-[4-[(4-fluorophenyl)methyl]phenoxy]ethyl]-4-piperidine-carboxamide;
N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-yl]acetamide;
N-[2-[4-(phenylmethyl)phenoxy]ethyl]cyclohexanamine, monohydrochloride;
N-[2-[4-(phenylmethyl)phenoxy]ethyl]cyclopentanamine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine-4-carboxamide;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-piperidine-carboxamide;
1-[3-[4-(phenylmethyl)phenoxy]propyl]-3-piperidine-carboxamide;
ethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylate, monohydrochloride;
8-[2-[4-(phenylmethyl)phenoxy]ethyl]-1,4-dioxa-8-azaspiro[4.5]-decane, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidinol, monohydrochloride;
N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-yl]-2-benzo[b]furancarboxamide;
ethyl 3-[[[1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine-4-yl]-carbonyl]amino]propanoate;
1-[3-(4-phenoxyphenoxy)propyl]-3-piperidinecarboxamide;
1-[3-(4-phenoxyphenoxy)propyl]-4-piperidinecarboxamide;
1-[2-(4-phenoxyphenoxy)ethyl]-4-piperidinecarboxamide;
1-[2-(4-phenoxyphenoxy)ethyl]-3-piperidinecarboxamide;
ethyl 1-[2-(4-phenoxyphenoxy)ethyl]-4-piperidine-carboxylate, monohydrochloride;
N-methyl-1-[2-(4-phenoxyphenoxy)ethyl]-4-piperidine-carboxamide;
4-[2-[4-(phenylmethyl)phenoxy]ethyl]morpholine, monohydrochloride;
1-[3-[4-(phenylmethyl)phenoxy]propyl]pyrrolidine;
1,1-dimethylethyl 1-[3-[4-(phenylmethyl)phenoxy]propyl]-L-prolinate;
phenylmethyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
methyl 4-oxo-1-[3-[4-(phenylmethyl)phenoxy]propyl]piperidine-3-carboxylate;
1,1-dimethylethyl 1-[3-[4-(phenylmethyl)phenoxy]propyl]piperidine-4-carboxylate;
ethyl N-[3-[4-(phenylmethyl)phenoxy]propyl]glycinate;
ethyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
phenylmethyl 3-[[2-[4-(phenylmethyl)phenoxy]ethyl]amino]propanoate;
methyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
1,1-dimethylethyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
ethyl 1-[3-[4-(phenylmethyl)phenoxy]propyl]piperidine-3-carboxylate;
ethyl 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-piperidine carboxylate;
ethyl beta-[[2-[4-(phenylmethyl)phenoxy]ethyl]amino]-3-pyridinepropanoate;
ethyl 3-[4-[4-(phenylmethyl)phenoxy]butylamino]propanoate;
phenylmethyl 3-[[4-[4-(phenylmethyl)phenoxy]butyl]amino]-propanoate;
ethyl 3-[[5-[4-(phenylmethyl)phenoxy]pentyl]amino]propanoate;
methyl 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidineacetate;
methyl 1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidinecarboxylate;
1-(hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrazin-1-yl]-ethanone, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carbonitrile, monohydrochloride;
1-[[2,3-dihydro-5-(phenylmethyl)benzofuran-2-yl]methyl]-4-piperidinecarboxamide;
ethyl 1-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-4-piperidine carboxylate, monohydrochloride;
(+)-1-[[2,3-dihydro-2-methyl-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]pyrrolidine, monohydrochloride;
(+)-1-[[2,3-dihydro-3-methyl-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-4-piperidinecarboxamide;
2,3-dihydro-5-(phenylmethyl)-2-(1-pyrrolidinylmethyl)furo[2,3-b]-pyridine, dihydrochloride;
(+)-1-[[5-(phenylmethyl)furo[2,3-b]pyridin-2-yl]methyl]-4-piperidine carboxamide;
1-[[2,3-dihydro-5-phenoxybenzo[b]furan-2-yl]methyl]pyrrolidine, monohydrochloride;
1-[[2,3-dihydro-5-phenoxybenzo[b]furan-2-yl]methyl-4-piperidinecarboxamide;
ethyl 1-[(2,3-dihydro-5-phenoxybenzo[b]furan-2-yl)-methyl]-4-piperidinecarboxylate, monohydrochloride;
(+)-1-[[3,4-dihydro-6-(phenylmethyl)-2H-benzopyran-2-yl]methyl]-4-piperidine, monohydrochloride carboxamide;
1-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-N-methyl-4-piperidine carboxamide;
1-[(2,3-dihydro-5-phenoxybenzo[b]furan-2-yl]methyl]-N-methyl-4-piperidinecarboxamide;
2S-alpha-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-alpha-pyridinecarboxamide;
N-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidinecarboxamide;
[[2,3-dihydro-5-(phenylmethyl)benzofuran-2-yl]methyl]-1-pyrazinecarboxamide;
4-[2-[4-(phenylmethyl)phenoxy]ethyl]-4H-imidazo[4,5-b]pyridine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-imidazo[4,5-b]pyridine;
3-[2-[4-(phenylmethyl)phenoxy]ethyl]-3H-imidazo[4,5-b]pyridine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-benzimidazole;
5-[2-[4-(phenylmethyl)phenoxy]ethyl]-5H-imidazo[4,5-c]pyridine, hydrate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-imidazo[4,5-c]pyridine;
3-[2-[4-(phenylmethyl)phenoxy]ethyl]-3H-imidazo[4,5-c]pyridine;
3-[3-[4-(phenylmethyl)phenoxy]propyl]-3H-imidazo[4,5-b]pyridine;
1-[3-[4-(phenylmethyl)phenoxy]propyl]-1H-imidazo[4,5-b]pyridine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-pyrrolol[3,2-b]pyridine;
1-[3-(4-phenoxyphenoxy)propyl]-1H-benzimidazole;
1-[2-(4-phenoxyphenoxy)ethyl]-1H-benzimidazole;
1-[2-[4-(phenylmethoxy)phenoxy]ethyl]-1H-benzimidazole;
3-[2-[4-(phenylmethoxy)phenoxy]ethyl]-3H-imidazo[4,5-b]pyridine;
1-[2-[4-(phenylmethoxy)phenoxy]ethyl]-1H-imidazo[4,5-b]pyridine;
4-[2-[4-(phenylmethoxy)phenoxy]ethyl]-4H-imidazo[4,5-b]pyridine;
3-[2-[4-(phenylmethoxy)phenoxy]ethyl]-3H-imidazo[4,5-c]pyridine;
1-[2-[4-(phenylmethoxy)phenoxy]ethyl]-1H-imidazo[4,5-c]pyridine;
5-[2-[4-(phenylmethoxy)phenoxy]ethyl]-5H-imidazo[4,5-c]pyridine;
3-[2-(4-phenoxyphenoxy)ethyl]-3H-imidazo[4,5-b]pyridine;
1-[2-(4-phenoxyphenoxy)ethyl]-1H-imidazo[4,5-b]pyridine;
4-[2-(4-phenoxyphenoxy)ethyl]-4H-imidazo[4,5-b]pyridine;
5-[2-(4-phenoxyphenoxy)ethyl]-5H-imidazo[4,5-c]pyridine;
1-[2-(4-phenoxyphenoxy)ethyl]-1H-imidazo[4,5-c]pyridine;
3-[2-(4-phenoxyphenoxy)ethyl]-3H-imidazo[4,5-c]pyridine;
3-[3-(4-phenoxyphenoxy)propyl]-3H-imidazo[4,5-b]pyridine;
1-[3-(4-phenoxyphenoxy)propyl]-1H-imidazo[4,5-b]pyridine;
4-[3-(4-phenoxyphenoxy)propyl]-4H-imidazo[4,5-b]pyridine;
3-[3-(4-phenoxyphenoxy)propyl]-3H-imidazo[4,5-c]pyridine;
5-[3-(4-phenoxyphenoxy)propyl]-1H-imidazo[4,5-c]pyridine;
5-[3-(4-phenoxyphenoxy)propyl]-5H-imidazo[4,5-c]pyridine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-imidazole, monohydrochloride;
2,3,6,7-tetrahydro-1,3-dimethyl-7-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-purine-2,6-dione;
3-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]-3H-imidazo[4,5-b]pyridine;
1-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]-1H-imidazo[4,5-b]pyridine;
3-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]-3H-imidazo[4,5-c]pyridine;
1-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]-1H-imidazo[4,5-c]pyridine;
5-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]-5H-imidazo-[4,5-c]pyridine;
3-[3-[4-(phenylmethyl)phenoxy]propyl]-3H-imidazo[4,5-c]pyridine;
1-[3-[4-(phenylmethyl)phenoxy]propyl]-1H-imidazo[4,5-c]pyridine;
5-[3-[4-(phenylmethyl)phenoxy]propyl]-5H-imidazo[4,5-c]pyridine;
7-[2-[4-(phenylmethyl)phenoxy]ethyl]-7H-purine;
9-[2-[4-(phenylmethyl)phenoxy]ethyl]-9H-purine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-purine;
3-[2-[4-(phenylmethyl)phenoxy]ethyl]-3H-purine, monohydrochloride;
3-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-3H-imidazo[4,5-b]pyridine, monohydrochloride;
1-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-1H-imidazo[4,5-b]pyridine;
4-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-4H-imidazo[4,5-b]pyridine, hydrochloride;
3-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-3H-1,2,3-triazolo[4,5-b]pyridine;
2-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-2H-1,2,3-triazolo[4,5-b]pyridine;
1-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl-1H-1,2,3-triazolo[4,5-b]pyridine;
2-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-2H-1,2,3-triazolo[4,5-c]pyridine, monohydrochloride;
1-[[2,3-dihydro-5-(phenylmethyl)benzo[b]furan-2-yl]methyl]-1H-1,2,3-triazolo[4,5-c]pyridine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-benzimidazole-5-amine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-benzimidazole-6-amine;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-imidazo[4,5-b]pyridinium 4-oxide;
3-[2-[4-(phenylmethyl)phenoxy]ethyl]-3H-imidazo[4,5-c]pyridinium, 5-oxide;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-imidazo[4,5-c]pyridinium, 5-oxide;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2-pyrrolidine-methanol, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidinol;
hexahydro-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-1H-azepine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]azocine, monohydrochloride;
2,5-dimethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrrolidine, monohydrochloride;
2S-(methoxymethyl)-1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrrolidine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine, monohydrochloride;
2,6-dimethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]propyl]piperidine, monohydrochloride;
hexahydro-1-[2-[4-(phenylmethyl)phenoxy]propyl]-1H-azepine, monohydrochloride;
[2-[4-(phenylmethyl)phenoxy]butyl]pyrrolidine, monohydrochloride;
2-[4-(phenylmethyl)phenoxy]ethyl]-1-[2-phenylmethyl]pyrrolidine, monohydrochloride;
ethyl beta-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]-4-pentynoate;
ethyl beta-[[2-[4-(phenylmethyl)phenoxy]ethyl]amino]-4-pentynoate;
phenylmethyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl](2-propenyl)amino]propanoate;
ethyl[[4-[4-(phenylmethyl)phenoxy]butyl](2-propenyl)amino]propanoate;
ethyl 3-[methyl-[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
methyl 3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate, hydrate;
ethyl 3-[[3-[4-(phenylmethyl)phenoxy]propyl](pyridin-3-ylmethyl)amino]propanoate;
ethyl [methyl[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoate, triethylamine salt; 1,1-dimethyl-3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanol;
phenylmethyl 2,2-dimethyl-3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylic acid hydrazide;
N-[2-(aminocarbonyl)ethyl]-1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidinecarboxamide;
N-methyl-3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanamide;
3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanamide;
1-[4-morpholinyl)-3-[(3-[4-(phenylmethyl)phenoxy]propyl]amino]-1-propanone;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidine-carboxamide;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidine-acetamide;
[1-[2-[4-(phenylmethyl)phenoxy]ethyl]-2S-pyrrolidin-2-yl]methyl N-phenylcarbamate;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidine-carboxylic acid, monohydrochloride, hydrate;
1-[3-[4-(phenylmethyl)phenoxy]propyl]-2S-pyrrolidine-2-carboxylic acid;
3-[[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
2-methyl-3-[methyl[3-[4-(phenylmethyl]propyl]amino]propanoic acid;
3-[[4-[4-(phenylmethyl)phenoxy]butyl]amino]propanoic acid;
3-[methyl[3-[4-(phenylmethyl)phenoxy]propyl]amino]propanoic acid;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-3-pyrrolidinamine, dihydrochloride;
N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrrolidin-3-yl]urea;
alpha-chloro-N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrrolidin-3-yl]acetamide, monohydrochloride;
1-[2-[4-(phenylmethyl)phenoxy]ethyl]-4-piperidinamine;
N-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-yl]urea;
hexahydro-1-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrazine, dihydrochloride;
hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]-1-pyrazinethioamide;
hexahydro-4-[2-[4-(phenylmethyl)phenoxy]ethyl]-1-pyrazinecarboxamide;
hexahydro-1-methylsulfonyl-4-[2-[4-(phenylmethyl)phenoxy]ethyl]pyrazine;
N-[2-alpha-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-beta-yl]acetamide;
4-hydroxy-cis-2-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine, monohydrochloride;
2-[4-(phenylmethyl)phenoxy]ethanamine, monohydrochloride;
(xc2x1) ethyl 2-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine-4-carboxylate;
phenylmethyl 3-[[3-(4-phenoxyphenoxy)propyl]amino]propanoate;
phenylmethyl 3-[methyl[3-(4-phenoxyphenoxy)propyl]amino]propanoate;
methyl 8-[2-[4-(phenylmethyl)phenoxy]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylate;
3-[(3-[4-phenoxyphenoxy)propyl]amino]propanoic acid;
ethyl 1-[2-[4-phenoxyphenoxy]ethyl]piperidine-4-acetate, monohydrochloride;
ethyl 1-[2-[[5-(phenylmethyl)thien-2-yl]oxy]ethyl]piperidine-4-carboxylate;
3-(methyl[3-[4-phenoxyphenoxy)propyl]amino]propanoic acid;
phenylmethyl 3-[[4-[4-phenoxyphenoxy)butyl]amino]propanoate;
5-[1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-yl]-1H-tetrazole;
(cis)-2R,6-dimethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine-4-carboxamide;
3-[[4-(4-phenoxyphenoxy)butyl]amino]propanoic acid;
ethyl 1-[2-[4-[[3-fluorophenyl)methyl]phenoxy]ethyl]piperidine-4-carboxylate;
ethyl 1-[2-[4-(2-thienylmethyl)phenoxy]ethyl]piperidine-4-carboxylate;
3-[[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoic acid, monohydrochloride;
methyl 3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoate;
3-[methyl[3-[4-(2-thienylmethyl)phenoxy]propyl]amino]propanoic acid, monohydrochloride;
1-[2-[4-phenoxyphenoxy]ethyl]piperidine-4-carboxylic acid, monohydrochloride;
methyl 3-[3-[4-[(4-fluorophenyl)methyl]phenoxy]propyl]methylamino]propanoate;
ethyl 1-[2-[4-[(4-fluorophenyl)methyl]phenoxy]ethyl]piperidine-4-carboxylate;
ethyl 1-[2-[4-(3-thienylmethyl)phenoxy]ethyl]piperidine-4-carboxylate;
methyl 3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoate;
5-[2-methyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidin-4-yl]-1H-tetrazole, monohydrate;
methyl 3-[[3-[4-(4-fluorophenoxy)phenoxy]propyl]methylamino]propanoate;
1-[2-[4-[(4-fluorophenyl)methyl]phenoxy]ethyl]piperidine-4-carboxylic acid, monohydrochloride;
1-[2-[4-(3-thienylmethyl)phenoxy]ethyl]piperidine-4-carboxylic acid, monohydrochloride;
3-[methyl[3-[4-(3-thienylmethyl)phenoxy]propyl]amino]propanoic acid, monohydrochloride;
ethyl 1-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]piperidine-4-carboxylate, monohydrochloride;
1-[2-[4-(4-fluorophenoxy)phenoxy]ethyl]piperidine-4-carboxylic acid, monohydrochloride;
1-[2-[4-[(3-fluorophenyl)methyl]phenoxy]ethyl]-4-carboxylic acid, monohydrochloride;
5-phenylmethyl-2-[2-(1-pyrrolidinyl)ethoxy]pyridine;
methyl(cis)-2R,6-dimethyl-1-[2-[4-(phenylmethyl)phenoxy]ethyl]piperidine-4-carboxylate;
ethyl 3-[[4-[4-phenoxyphenoxy]butyl]amino]propanoate;
1-[2-[4-(2-thienylmethyl)phenoxy]ethyl]piperidine-4-carboxylic acid, monohydrochloride.
The compounds of the invention are prepared from readily available starting materials by any of the following alternate processes in a conventional manner. The following reaction schemes describe methods which can be employed for preparing the compounds of formula I, including starting materials, intermediates and reaction conditions. The following terms, as used herein, have the definitions which are given in the table below.
Preparation of the compounds of formula I may be accomplished via one or more of the synthetic schemes which are set forth hereinafter.
Schemes 1-4 depict various methods for preparing substituted phenols of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94OH, wherein Ar1 and Ar2are independently phenyl, substituted phenyl, pyridyl or thienyl moieties. 
Scheme 1 shows methods for producing compounds of the formula Ar1xe2x80x94CH2xe2x80x94Ar2xe2x80x94OH wherein Ar2 is a phenyl moiety. Scheme 1 shows two related precursor compounds (1, 2) which may be employed as a starting material. Compound 1 is an alkylated or silylated derivative of p-bromophenol. A convenient starting material 1 is 1-bromo, 4-methoxyphenol (i.e., R is methyl). On the other hand, compound 1 may be readily provided by silylation of p-bromophenol with t-butyldiphenylsilyl chloride or other silylating agents (see, Example 2). In either event, compound 1 may be reacted with tert-butyl lithium in an ethereal solvent at low temperature, such as in THF at xe2x88x9278xc2x0 C., and quenched with an arylaldehyde (Ar1CHO) to yield compound 3. Similarly, starting from compound 2, a p-methoxybenzaldehyde or a silylated derivative of p-hydroxybenzaldehyde (see, Example 1) may be employed. Compound 2 may be reacted with an aryl lithium (Ar1Li) or aryl magnesium bromide (Ar1MgBr) to yield compound 3. Regardless of which route is chosen, compound 3 is reduced, e.g., by hydrogenation over palladium on carbon or with triethylsilane, to provide compound 4. Compound 4 is readily deprotected using TBAF in THF (desilylation) or using BBr3 in methylene chloride at xe2x88x9278xc2x0 C. (dealkylation) to provide compound 5.
Compounds 5 of the formula Ar1xe2x80x94CH2xe2x80x94Ar2xe2x80x94OH, wherein Ar1 is a para-halogen-substituted phenyl moiety, such compounds are preferably provided by sodium borohydride reduction of a compound 6 to provide compound 3, followed by hydrogenation as described above to afford compound 5. 
Scheme 2 depicts the preparation of compounds of formula Ar1xe2x80x94CH2xe2x80x94Ar2xe2x80x94OH wherein xe2x80x94Ar2xe2x80x94OH is a substituted phenol R8(R9)PhOH and R8 and R9 are as defined hereinbefore. In this reaction sequence, the substituted phenol 7 is reacted with a suitable aryloyl chloride to give the intermediate aryloyl ester (not shown) which is heated to a temperature of about 160xc2x0 C. in the presence of AlCl3 to promote Fries rearrangement which affords the desired compound 8, having the specifically substituted Ar2 moiety. Compound 8 may be reduced utilizing the two-step reduction sequence (Scheme 1, steps (c) and (d)) to provide compound 9. 
Scheme 3 shows a general method for the preparation of phenols of the formula Ar1xe2x80x94Oxe2x80x94Ar2xe2x80x94OH wherein Ar1 is a substituted phenol. Ar1 may be any substituted arylphenol which is capable of reacting with 4-iodoanisole in an Ullman coupling reaction. See, A. Moroz, et al., Russ. Chem. Rev. 43, 679 (1974). The Ullman reaction is carried out conventionally in the presence of activated copper or copper iodide at a temperature of about 150xc2x0 C. to 200xc2x0 C. A particularly preferred substituted phenol for providing compounds of the present invention having a substituted Ar1 moiety is 4-fluorophenol. 
Scheme 4 shows a synthesis for making compounds of the formula Ar1xe2x80x94O-pyridyl-OH (i.e., Ar2 is pyridyl). In the reaction, 2-amino-5-bromopyridine is combined with an excess of a suitable phenol (Ar1OH) and coupled utilizing the Ullman reaction, essentially as described with reference to Scheme 3, to provide the aminopyridine derivative 10. Compound 10 is diazotized with sodium nitrite/H2SO4/H2O and decomposed to afford compound 11. 
Scheme 5 shows the preparation of compounds of the general formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Yxe2x80x94Rxe2x80x94Z (Formula I) from compounds of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94YH (12) (wherein R is ethylene, Y is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94Sxe2x80x94, R20 and R21 are independently hydrogen or lower alkyl, and wherein Ar1, Q, Ar2, and Z are previously defined). Compounds of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94YH may be made in accordance with Schemes 1-4 or may be obtained commercially, including 4-hydroxydiphenylmethane, 4-hydroxybenzophenone, 4-benzyloxyphenol, etc.
A compound of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94YH (12) may be converted into a compound of the present invention via alkylation with any of a variety of chloroethylaminoalkyl analogs, wherein the aminoalkyl moiety may be cyclic or acyclic. Where Q is carbonyl, the carbonyl moiety of compound 13 is reduced to xe2x80x94CH2xe2x80x94 as depicted in steps (c) and (d) of Scheme 1 to afford compound 14. 
Scheme 6 shows a presently preferred method for preparing compounds of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Oxe2x80x94Rxe2x80x94Z, wherein R is a linear alkylene moiety. Scheme 6 depicts alternate reaction pathways for adding an alkylene linker moiety, R (as defined in formula I) to the phenolic hydroxyl group of compound 15, which alkylene linker terminates in a reactive halogen or tosylate group. In the pathway which provides compound 17 wherein R is ethylene (i.e., R provides a 2 carbon linker) compound 15 is reacted with ethylene carbonate in DMF in the presence of nBu4NBr to give compound 16 which is subsequently reacted with tosylchloride in dichloromethane and pyridine to provide compound 17 wherein X is xe2x80x94OTs.
Where R is a C3-C6 alkylene moiety, compound 15 is reacted with CH2Clxe2x80x94(CH2)axe2x80x94CH2Br (wherein m is 1-4) in the presence of DMF and NaH to provide compound 17 wherein X is Cl.
Compound 17 is reacted with a nitrogen containing compound of the formula ZH in DMF at 60xc2x0 in the presence of K2CO3, to give compound 18, wherein Z is an acyclic amine moiety, a monocyclic or bicyclic amine moiety or a monocyclic or bicyclic heteroaromatic moiety as defined hereinbefore with reference to compounds of Formula I. 
Scheme 7 describes a method for making compounds of the Formula I wherein Ar2 is thiophene. The synthesis entails reaction of 2-bromothiophene or 2-iodothiophene with a terminally substituted diol of the formula CH2OHxe2x80x94(CH2)mxe2x80x94CH2OH wherein m=0-4. Such diols include ethylene glycol, 1,3 propanediol, 1,4 butanediol and 1,5 pentanediol and 1,6 hexanediol. The reaction is carried in the presence of copper (II) oxide in the diol as solvent at 120xc2x0 C. to afford compound 19. Compound 19 is lithiated on the thiophene ring with nBuLi (2 equivalents) in THF at xe2x88x9278xc2x0 C. to produce the corresponding 5-lithio anion of compound 19 which is then quenched with a suitable arylmethylbromide (Ar1CH2Br), for example, benzylbromide, to afford compound 20, which may be converted into compound of Formula I via tosylation followed by displacement as described in Scheme 6 (20xe2x86x9221xe2x86x9222). 
Scheme 8 describes the synthesis of compounds of Formula I wherein xe2x80x94Qxe2x80x94Ar2xe2x80x94 is xe2x80x9cxe2x80x94CH2O-phenyl-xe2x80x9d and Ar1 may be any of a variety of aryl moieities (see, for example, Table 13). The synthesis starts with a compound of Formula I wherein Ar1xe2x80x94Qxe2x80x94 is Ph-CH2xe2x80x94Oxe2x80x94 (23), and debenzylates the compound, employing H2, 4% Pd/C, EtOH, to afford intermediate phenol 24 which is alkylated in the presence of NaH in DMF with any of a variety of arylmethybromides to afford compound 25. Suitable arylmethylbromides include, but are not limited to the arylmethylbromides enumerated with reference to Scheme 7. 
Scheme 9 generally depicts methods for preparing compounds of Formula I wherein Ar2 is a 2,5-disubstituted pyridinyl moiety. Such compounds of the present invention may be prepared starting from the acid chloride of 2-chloro-5-pyridine-carboxylic acid. The acid chloride 26 is combined with a suitable aryl compound (Ar1) and reacted under Friedel-Crafts acylation conditions to provide the chloropyridinyl containing ketone 27, which is reacted with a suitable hydroxyalkylamine of the formula HOxe2x80x94Rxe2x80x94Z, wherein R and Z are as defined hereinbefore, to yield compound 28 which is subject to a 2-step reduction (shown in steps (c) and (d) of Scheme 1) to provide compound 29 which is a compound of Formula I. 
Scheme 10 describes preparation of a variety of compounds of the formula HOxe2x80x94Rxe2x80x94Z 33 wherein R is alkylene and Z is defined hereinbefore. These compounds may be employed in the methods described in Scheme 9, step b. In Scheme 10, a benzyloxyalcohol 30 is converted into the corresponding tosylate 31 by reaction with tosylchloride in the presence of pyridine and methylene chloride at 0xc2x0 C. which is reacted with a secondary amine of the formula 
in DMF at 60xc2x0 C., in the presence of K2CO3 to provide compound 32. Compound 32 is hydrogenated (H2/Pd, ethanol) to afford compounds of the formula HOxe2x80x94Rxe2x80x94Z (33), wherein R is alkylene, and coupled to compounds of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94OH (see schemes 1-4) in the presence of diethylazodicarboxylate (DEAD) and triphenylphosphine in THF (O. Mitsunoba, Synthesis, 1, (1981)) to provide compound 34 which is a compound of Formula I.
In another of its embodiments the present invention entails the compound of the formula 
wherein r is 1 or 2, and Ar1, Q, X and Z are as defined hereinbefore. In this embodiment of the invention the compounds are rotationally constrained by fusion of a portion of the linker group R to the Ar2 moiety through a 5- or 6-membered fused ring (i.e., dihydrobenzofuran or tetrahydrobenzopyran). 
With reference to Scheme 11, compound 35 is alkylated in DMF in the presence of sodium hydride with allylbromide or a 2-methyl substituted allylbromide to afford the corresponding O-allyl ether (not shown), which is heated to 230xc2x0 C. in a Claissen rearrangement reaction, followed by oxidative cyclization with metachloroperbenzoic acid (mCPBA) in chloroform to yield the alcohol 36. Alcohol 36 is reacted with tosyl chloride in pyridine/methylene chloride mixture at 0xc2x0 C. to afford the corresponding tosylate 37, which is then condensed (in DMF in the presence of potassium carbonate) with a primary or secondary amine, ZH, or an aromatic nitrogen containing heterocycle, ZH, wherein Z is define hereinbefore to afford compound 38 which is a compound of formula I. 
Scheme 12 shows a method for preparing compounds of the present invention from phenols of the formula 35. Phenol 35 can be transformed into tetrahydrobenzopyran analogs via the following six-step (steps (a)-(f)) procedure. In step (a), the phenol 35 is converted into its corresponding diethylcarbamate 39 employing diethylcarbamoylchloride, KH, and DMF. In step (b), the diethylcarbamate compound 39 is then ortho-lithiated (sec.butyllithium, Et2O, TMEDA) and quenched with DMF to afford aldehyde 40. The aldehyde 40 is reacted with allylmagnesium bromide in step (c) and the resulting alcohol 41 is reduced and deprotected in step (d) utilizing sulphur-trioxide/pyridine in THF, followed by addition of lithium aluminum hydride to afford phenol 42, which is substituted with but-3-ene in the position ortho to the phenolic hydroxyl. Phenol 42 is oxidatively cyclized in two steps, via epoxide 43 utilizing mCPBA in CHCl2, followed by acid-catalyzed epoxide ring opening with tosic acid in CHCl3 in step (f) to afford the tetrahydrobenzopyran containing alcohol 44. Alcohol 44 may be further converted into compounds of the formula I, via formation of the corresponding tosylate 45, followed by displacement with compounds of the formula ZH, as described in Scheme 6. 
Scheme 13 represents an alternative procedure to that shown in Scheme 6 for attaching an hydoxyethylene moiety to phenols of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94OH (15). In the methods depicted in Scheme 13, phenol 15 is alkylated with t-butylbromoacetate in THF in the presence of sodium hydride to yield t-butyl ester 47, which is then reduced with LAH in THF to afford the hydroxyethylene substituted analogs, Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OH 48.
In an analogous reaction sequence, t-butyl ester 47 may be alpha-alkylated via reaction with LDA in THF at xe2x88x9278xc2x0 C., followed by quenching with an alkylhalide (R22X) at xe2x88x9278xc2x0 C. The resulting alpha-substituted ester 49 is reduced (LAH in THF) to afford compound 50 having a branched alkylene moiety.
The synthetic route described in Scheme 13 provides compounds which may be employed in steps (c) and (d) of Scheme 6 to provide compounds of Formula I having a linear or branched alkylene moiety. 
Scheme 14 describes yet another synthetic pathway utilizing t-butyl ester 49 as a starting material for the preparation of compounds of Formula I. Here, the t-butyl ester is deprotected with trifluoroacetic acid in methylene chloride to afford the corresponding acid 51 which is then coupled to an amine compound of the formula 
using DSC in pyridine and DMF to yield amide 52. As depicted, R20 and R21 are independently hydrogen or alkyl and optionally the defined amine may be a cyclic amine. Amide 52 may be reduced with lithium aluminum hydride in THF to give compound 53, provided that neither R20 nor R21 is (nor comprises) a functional moiety, such as an amide, ester, nitrile or the like, which is reactive toward LAH. Compound 53 is a compound of formula I. 
wherein 
does not contain functionality reactive towards LAH reduction.
Scheme 15 depicts a preferred method for preparing compounds of Formula I which comprise sterically hindered amines such as 2,6-dimethylpiperidine, 2,5-dimethylpyrrolidine and the like. In this method, the sterically hindered amine is acylated with chloroacetylchloride in methylene chloride/pyridine at 0xc2x0 C. to afford xe2x88x9dxcex1-chloroamide 54. Alkylation of a phenol of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94OH with the xe2x88x9d-chloroamide 54 [DMF,NaH] affords amide 55. Provided that the amide group of compound 55 is the only moiety which is reactive toward LAH, reduction of compound 55 with LAH in THF provides a compound 56 which is a compound of Formula I. 
Scheme 16 describes yet another method for preparation of compounds of Formula I in which compound 15 is alkylated with a bromodimethyl acetal (60) in DMF in the presence of NaH to afford acetal 57. Subsequent deprotection with toluene-4-sulfonic acid in THF/H2O affords intermediate aldehyde 58 which is reductively aminated [EtOH, KOH, NaBH3CN] with an amine of the formula HNR1R2 to afford compound 59 which is a compound of Formula I. 
Scheme 17 shows a preferred method for preparing compounds 63 and 64 employing an intermediate chloride 60 as an alternative to using the corresponding tosylate. Compound 60 is aminated with a 100-fold excess of methylamine in acetonitrile at 60xc2x0 C.-70xc2x0 C. to afford secondary amine 61. While compound 61 is a compound of Formula I, compound 61 may be further elaborated by reaction with a benzylacrylate ester or a methylacrylate ester to provide compound 62 which is also a compound of Formula I. Where the ester 62 is a benzyl ester, it may be converted into its corresponding acid 63 by hydrogenation (H2/Pd/EtOH at 2 psi); and where ester 62 is alkyl ester, it may be converted into its corresponding acid as the hydrochloride salt 64 via hydrolysis with 6N HCl in THF at 60xc2x0 C.
Among the preferred compounds of the present invention are those in which the nitrogen-containing moiety (i.e., Z, as defined herein) comprises at least one polar moiety, such as a carboxylic acid or ester moiety or a carboxamide, acylhydrazide, alkylamide or alanineamide moiety or the like. 
R25=alkyl, branched alkyl, aryl.
Scheme 18 illustrates further modification of a compound 65 which is also referred to herein as a xcex2-alanine-based compound of Formula I. Compound 65, which is representative, is reductively aminated with a C1-C4 aldehyde or ketone included but not limited to formaldehyde, acetaldehyde, 1-propanal, acetone, methyl-ethyl ketone and the like to provide compound 66 which is a compound of Formula I. Compound 66 may optionally be converted tertiary alcohol 67 (also a compound of Formula I) by reaction with methylmagnesium bromide in ether at 0xc2x0 C. 
Scheme 19 illustrates a method for introducing one or two methyl substitution(s) into the backbone of the xcex2-alanine moiety of compound 62. Compound 62 may be sequentially alpha-methylated by reaction with LDA in THF at xe2x88x9278xc2x0 C. followed by quenching with methyliodide to afford compound 68 or compound 69.
Schemes 20 and 21 show modification of a compound 70 comprising an ester-containing Z group to produce compound 71 or compound 72 possessing a variety of polar substitutions. 
Scheme 20 depicts the modification of a compound 70 which comprises an ester moiety in which the ester is modified by the addition of a nucleophile such as an amine or hydrazine to provide compound 71 as shown in the xe2x80x9cExemplified Reactionsxe2x80x9d set forth in equations (a)-(h) of Scheme 20. 
Scheme 21 shows the conversion of compound 70 which comprises an ester moiety to corresponding acid 72 via one of three reactions: (1) basic hydrolysis; (2) acidic hydrolysis, which is preferred where R is a lower alkyl or benzyl; or (3) hydrogenolysis over palladium on carbon in EtOH, which is especially preferred where R is benzyl.
Schemes 22 and 23 show alternative methods for preparing a nitrile containing compound 74 which is a compound of Formula I and which conveniently may be employed as an intermediate in the preparation of various compounds of the present invention described in Scheme 24 below. 
In Scheme 22 dehydration of a carboxamide containing compound 73 with trifluoracetic anhydride in pyridine/THF at 0xc2x0 C. affords the corresponding nitrile containing compound 74. 
Scheme 23 shows a synthetic route to compound 74 which is analogous to Scheme 22. In Scheme 23, the t-butoxycarbonyl-protected (i.e., BOC-protected) piperidine amide 75 is dehydrated using the conditions described in Scheme 22 (TFAA/pyridine) to afford protected nitrile 76. Deprotection of nitrile 76 with trifluoroacetic acid in methylene chloride at 0xc2x0 C. affords the corresponding secondary amine 77 which may be coupled to compound 17 essentially as described in Scheme 6 (step d) to afford nitrile-containing compounds of the present invention, which may be utilized as described in Scheme 24. 
Scheme 24 shows several reaction pathways which may be used to modify the nitrile moiety of compound 78 to afford a variety of compounds of the present inventions. In step (a) the nitrile moiety of compound 78 is condensed with hydroxylamine in an alcoholic solvent such as ethanol, propanol, butanol, or the like to afford the corresponding hydroxyamidine 79 which is a compound of the present invention as well as an intermediate for step (b) of this Scheme. Thus, in step (b), hydroxyamidine 79 may be hydrogenated in ethanol over palladium on carbon to afford the corresponding amidine 80 which is a compound of the present invention. Alternatively, hydroxyamidine 79 may be cyclized with phosgene in toluene at 60xc2x0 C. to yield 81 which is a compound of the present invention. Scheme 21 furthers shows, in step d, reacting nitrile 78 with trimethyl-tin azide in xylene at 130xc2x0 C. to afford the corresponding tetrazole containing compound 82 which is a compound of the present invention. 
Scheme 25 illustrates modification of compounds having a cyclic amine moiety derivatized with an acetamide group (compound 83) to convert the acetamide moiety to a primary amine (HCl/EtOH/H2O 80xc2x0-100xc2x0 C.) to provide compound 84 which, in turn, may be modified to a urea moiety (TMSxe2x80x94NCO) to provide compound 85 or to an alpha-chloroamide moiety to provide compound 86. Compounds 84, 85 and 86 are compounds of the present invention.
Compounds of the present invention containing a piperazine moiety, compound 87, may be derivatized in essentially the same manner as described in Scheme 24 to yield derivatized piperazine compounds which include methylsulfonamide-containing compound 88, thiourea-containing compound 89 or urea-containing compound 90, as illustrated in Scheme 26. 
Scheme 27 shows methods for preparing compounds of the invention having a 4-substituted 2-methyl piperadine moiety. In Scheme 27, di-protected 4-piperadol 91 is methylated in the 2-position using the method of P. Beak, et al., J. Org. Chem. 58, 1109 (1993). The 2-methyl derivative 92 is deprotected using trifluoracetic acid in methylene chloride at 0xc2x0 C. to yield the secondary amine 93 which, in turn, is coupled to a compound of the formula Ar1xe2x80x94Qxe2x80x94Ar2xe2x80x94CH2CO2H (compound 51, wherein R is hydrogen) using the method described in Scheme 14, step (b). The resulting amide 94 may be reduced and desilylated in one step with LAH in THF at room temperature to afford the trans di-substituted piperadine 95 which is a compound of the present invention.
Alternatively, amide 94 may be desilylated (TBAF) to afford alcohol 96 which is subjected to a four-step reaction sequence (steps (f)(1)-(f)(4)) to afford cis 2-methyl, 4-amino piperadine 97.
The four-step reaction scheme consists of reacting the alcohol 96 with TsCl in methylene chloride/pyridine at 0xc2x0 C. to give the corresponding tosylate which is displaced with sodium azide in DMF (60xc2x0-80xc2x0 C.) to afford the corresponding azide having inverted stereochemistry (i.e., transxe2x86x92cis). The azide is hydrogenated at atmospheric pressure in methanol over 4% palladium on carbon to afford the corresponding amine of the formula 
the amide function of which is reduced with LAH in THF at room temperature to afford compound 97. Optional acylation of the 4-amino moiety of compound 97 affords compound 98. 
Scheme 28 shows methods for making cis 2-methyl, 4-substituted piperidines, 100, (which are compounds encompassed within xe2x80x9cZHxe2x80x9d as used herein) which compounds can be coupled in a coupling reaction as described in Scheme 6 to afford compounds of formula I. Scheme 28 starts with commercially available 2-chloro-6-methyl pyridine-4-carbonylchloride (Maybridge Chem.) which is reacted with one of the following: (1) ammonium hydroxide; (2) methanol; or (3) methylamine. The reactions each may be carried out in methylene chloride at 0xc2x0 C. to afford a substituted pyridine of the formula 99 wherein R is (1) NH2; (2) OCH3; or (3) NHCH3, respectively. Compound 99 is hydrogenated over ruthenium catalyst (e.g. 5% ruthenium on charcoal) at 140xc2x0 C. at 60 psi to afford a cis 2-methyl,4-substituted piperidine 100. 
Scheme 29 shows methods for preparing cis 2,6 dimethyl, 4-substituted piperidines 103 and 105 (which compounds are also encompassed within xe2x80x9cZHxe2x80x9d as defined herein) which may be coupled in a coupling reaction as described in Scheme 6 to afford compounds of the present invention. Scheme 29 starts from 2,6-dimethyl-4-cyanopyridine 101 which is prepared in accordance with the method of Feely, et al., JACS 81, 4004 (1959). Compound 101 is hydrolyzed using basic hydrogen peroxide in ethanol to afford primary amide 102 which, in turn, is hydrogenated under the conditions described in Scheme 28 to afford the corresponding tri-substituted piperidine 103.
Alternatively, primary amide 102 may be esterified using HCl(g) in methanol to afford the corresponding methylester 104 which, in turn, may be hydrogenated as described in Scheme 28 to afford the corresponding tri-substituted piperidine 105. 
Scheme 30 shows methods for preparing 2-methyl 4-substituted piperidines and 2,6-dimethyl 4-substituted piperidines 108 which can be coupled as described in Scheme 6 to afford compounds of the present invention. In Scheme 30, compound 106 may be prepared by the combination of the method of R. F. Evans et al., JOC 27, 1665 (1962), followed by the method of R. J. Martins et al., RECUEIL 86, 655 (1967). Compound 106 is acetylated using acetic anhydride and pyridine and the resultant acetamide 107 is hydrogenated under the conditions described in Scheme 28 to afford compound 108. 
Scheme 31 shows a method for preparing substituted tropones (referred to herein as xe2x80x9cZHxe2x80x9d) which tropones may be coupled in accordance with Scheme 6 to provide compounds of the present invention. In Scheme 28, tropone 109 (which may be derived from commercially available N-methyl tropone) is N-benzylated with benzylbromide in DMF in the presence of K2CO3 at 0xc2x0 C. to provide 110 which is homologated with the lithium anion derived from dimethylsilyldithiane (THF, nBuLi, 0xc2x0 C.) to give the dithiane adduct 111.
The dithiane adduct 111 is converted into the corresponding methyl ester using mercuric chloride-catalyzed hydrolysis in methanol to provide methyl ester 112 which is debenzylated via hydrogenation in methanol/concentrated hydrochloric acid over palladium hydroxide on carbon at 60 psi to afford carboxymethyl-substituted tropane 113. It should be understood that such carboxymethyl-substituted tropanes may be further modified in accordance with the method described in Schemes 20 and 21 to provide a wide variety of substituted tropones. 
Scheme 32 shows the preparation of 3-substituted pyrrolidine 119 from methy-1-benzyl-5-oxo-3-pyrrolidine carboxylate 114 which is commercially available. In step (a) of Scheme 32 compound 114 is reduced with LAH in THF at room temperature to afford alcohol 115, which is then reacted with thionyl chloride at reflux to give to the corresponding chloride 116. Compound 116 is then treated with aqueous sodium cyanide at 100xc2x0 C. for about 48 hours to yield the nitrile 117. Hydrolysis of nitrile 117 in methanolic HCl affords methyl ester 118, which may be debenzylated using hydrogen-transfer hydrogenation conditions (1,4 cyclohexadiene, methanol 10% Pd/C) to provide the 3-substituted pyrrolidine 119. 
Scheme 33 shows a 3-step procedure for the preparation of [2.2.1]-2-aza-bicycloheptane 123 from 2-(carbobenzyloxy) 2-azabicyclo[2.2.1]heptan-5-one 120. Compound 120 is prepared as described by F. Ivy Carroll, et al., J. Med. Chem. 35, 2184 (1992). Compound 120 is condensed with methyl(triphenylphosphoranylidene)acetate in THF at 50xc2x0-70xc2x0 C. to afford xcex1,xcex2 unsaturated ester 121. Reduction of compound 121 with magnesium in methanol affords the corresponding saturated ester 122. Compound 122 is decarbobenzyloxylated [5% Pd/C, MeOH, aq, HCl] to afford the corresponding amine 123. 
Scheme 34 shows the preparation of compounds of the present invention which are characterized as containing a 2-aza[2.2.1]bicyclo heptane or 2-aza[2.2.2]bicyclooctane moiety. Tosylate 124 is displaced with sodium azide in DMF to afford the corresponding azide 125. Azide 125 is reduced with LAH in THF to afford the corresponding primary amine 126. Primary amine 126 may be further condensed in an aza Diels-Alder reaction in the presence of either cyclopentadiene or 1,3 cyclohexadiene [40% aqueous formaldehyde, in 1N HCl] to afford azabicyclic alkenes 127 which may be hydrogenated in ethanol over 4% palladium on carbon at 5 psi to afford compounds 128. Compounds 126, 127 and 128 are compounds of the present invention. 
Scheme 35 describes preparation of compounds 133 of the invention having a 3-aza[3.2.1]bicyclo octane-7-methoxycarbonyl moiety. 5-norbornene-2-carboxylate is esterified in DMF containing methyl iodide and potassium carbonate. The resulting methyl ester 130 is dihydroxylated with catalytic osmium tetroxide in acetone/H2O using N-methylmorpholine oxide to recycle the catalyst. The resulting diol 131 is cleaved with aqueous sodium periodate in t-butanol to afford dialdehyde 132. Condensation of dialdehyde 132 with amine 126 in methanol followed by reduction with sodium cyanoborohydride affords compound 133 which is a compound of the invention.